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Harry, It's interesting all this talk about the EDSS score being the most important thing. If you remember from the Cochran report on Copaxone, the one thing that didn't fit their conclusion that C didn't work was the improvement in the EDSS score in the long term trial.

Personally I think the EDSS score is a mixed bag. I know my own has improved in the last 4 years. Watching my niece I'd say hers is up and down like a yo-yo. She'll go from a full body lockup to doing a 5 mile walk in a months time. I think it has to do with the amount of recovery time from the last attack.

Yes, EDSS can be a mixed bag but of all the ways they have of gauging how a patient is doing on a MS medication, it's the main way one can measure meaningful change. The other is looking at the symptoms such as fatigue, spasticity, cognitive function, etc. One of the big problems we found with the CRAB drugs was the patient not feeling any better, still suffering from all the symptoms and the disease continuing to progress. The docs continued to state that they found fewer lesions and a reduction of exacerbations but the patient continued to worsen!

I really don't know if Tysabri is going to follow this same path....a greater degree of reduced lesions and exacerbations but continued disease progression. Believe me, there is a lot of doubt lingering out there by some MS docs because of the lack of total data. Hopefully, within the next year many questions will be answered.

Harry

Last edited by HarryZ on Tue Nov 30, 2004 12:25 pm, edited 1 time in total.

You're right in the case of RRMS. Observations of EDSS would depend entirely on whether the subject is undergoing a relapse or is in remission. It's one of the things that makes MS such an infuriating condition.

The only thing that you can do in this case is measure a person when they're in the height of remission. That will give some indication of the underlying irretrievable disability. However 'height of remission' is a subjective term, equally difficult to quantify.

That brings me on to another issue with clinical trials. What constitutes a relapse? Many trials give percentages of relapse rates before and after treatment. How do you quantify a relapse? I have yet to find a definitive statement as to what qualifies as a relapse. How much do you have to deteriorate and for how long, before a relapse is confirmed? If the definition of relapse is subjective then surely the results of these trials are also subjective.

Uh oh.........you're getting detailed AND apparently finding the "loopholes" shall I call them, regarding clinical trials, etc. Be careful, you're about to enter my world here on the Board. NOW you might start getting that rotten fruit thrown at you that you were afraid of before!

EXACTLY MY POINT!!! Except I take forever to make the point! LOL (But that's because so many people want "proof" of how I came to my conclusions, etc., so I get longer and longer winded, as you see me do.)

As a matter of fact, and I'll say this simply because you know what I mean, and I don't have to "explain"......I said the exact same thing to my newest neuro last month (the Vanderbilt neuro). I said "You know, this is ALL purely subjective" (meaning any interpretation regarding MS). He laughed and said "You're exactly right."

That brings me on to another issue with clinical trials. What constitutes a relapse? Many trials give percentages of relapse rates before and after treatment. How do you quantify a relapse? I have yet to find a definitive statement as to what qualifies as a relapse. How much do you have to deteriorate and for how long, before a relapse is confirmed? If the definition of relapse is subjective then surely the results of these trials are also subjective.

E X A C T L Y !!!!!

Reduced lesion load and exacerbations, in my opinion, have been highly over-rated when it comes to clinical trial reporting. We know lesions don't correlate with symptoms and your thoughts on relapses show a vulnerability in quantifying the data in a trial. So with the absence of EDSS data from Tysabri, what was it that the FDA saw in Biogen's data that impressed them so much?

I can't help but think of Bertrand Russel's famous saying...

"The fact that an opinion has been widely held is no evidence whatsoever that it is not utterly absurd: indeed in view of the silliness of the majority of mankind, a widespread belief is likely to be more foolish than sensible"!

I start to wonder if the FDA "experts" are caught up in this scenario.

"The fact that an opinion has been widely held is no evidence whatsoever that it is not utterly absurd: indeed in view of the silliness of the majority of mankind, a widespread belief is likely to be more foolish than sensible"!

That's a GREAT quote!!!

I start to wonder if the FDA "experts" are caught up in this scenario.

I wouldn't have thought so a week or so ago when I wrote to the FDA........but needless to say, I now wonder the same thing as you!

Harry,
I am not against Tysabri, There is no doubt that it is more effective in controlling lesions than the interferons. How that fact relates to long term disability is unknown. I have my own convictions that dictate my own choices as far as long term efficacy is concerned, but I am definitely in a minority. The accepted medical wisdom is that MS is a T cell mediated condition. If that is true then Tysabri will most definitely help.

I can and will offer my own opinions and views but they always come with the caveat that they are mine alone. I will under no circumstances encourage someone to take a particular medication, nor will I try and discourage them. I am always willing to discuss, but will leave advice to qualified professionals which I most definitely am not.

The accepted medical wisdom is that MS is a T cell mediated condition. If that is true then Tysabri will most definitely help.

Yes, that has been the long accepted unproven theory. But one has to wonder these days after Barrett and Prineas discovered damaged myelin in that young girl who died from MS and saw no evidence of immunse system activity. Also, they have recently found evidence of MS in the grey matter of the brain which doesn't contain myelin. They are now starting to ask the big question....if the immune system isn't involved, what is causing this MS damage?

I can and will offer my own opinions and views but they always come with the caveat that they are mine alone. I will under no circumstances encourage someone to take a particular medication, nor will I try and discourage them. I am always willing to discuss, but will leave advice to qualified professionals which I most definitely am not.

The following couple of questions are to Al Sandrock, VP of Medical Affairs for Biogen Idec (he may have another title, as my memory is failing me!):

Question from Frank Savrile: Al, I was struck on page 15 of your presentation in the distribution slide of new and newly enlarging T2 lesions, how there is a mirror image almost between drug relative to placebo in 0 new lesions versus greater than or equal to 3. And I’m wondering, from historical studies, if you are look at this marker relative to EDSS score changes at two years in historical data, what has been seen in the past and how tightly correlative are these, and what can you say about that? Al Sandrock: That’s a tough question. First of all, I think the T2 lesion data with Tysabri is better than what we have seen with the interferons. Certainly, if you look at the mean number, the reduction in mean number, it is greater. The 80% number is greater than what we have seen with other drugs which are in the 60% range. The question about correlation between MRI measures of any type, actually, and EDSS is a tougher one. I think the correlation is modest. It partly depends on the stage of disease. If you take relapsing MS as we did in these trials, the correlation is much better than if you take, for example, people who have relapsing-secondary progressive MS where the correlation is quite poor. And those in the later stages of the disease, you can have a very strong effect on MRI and no effect on EDSS as we seen with the interferon trials in various stages of secondary progressive MS. I do think the correlation is pretty good in relapsing remitting MS which is largely what we studied here. That’s the best I can do with the answer at this point.

Q. Can you comment on the potential relationship between relapses and EDSS progression? Al Sandrock: Again, we have examples of drugs that are on the market now that have achieved the relapse endpoint in their Phase III trials, but were not able to achieve their disability endpoint in Phase III trials. We’ve looked, there was a recent paper published by Cutter and I think it was Loveland, looking at the Silvia Lori center where they collected MS trial data from a number of trials. And they looked at how many of the relapses actually end up with EDSS progression. It turns out that about 45% or so of relapses lead to a .5 change in EDSS. And about a 25% or 30% (I believe the numbers are in that range) of relapses lead to a 1 point change in EDSS, sustained. So, given that we have a very strong effect on relapses, and given that there is some correlation between relapses and EDSS progression, at least as seen in that study which had looked at a huge database, I predict that it would be hard [not to see EDSS improvement] … If we don’t get an effect on EDSS, we are going to have to rethink how we think about MS, because it would just be quite a surprise.

Seems that they is some validity to looking at MRIs and relapse rates! And can anyone guess what a 66% reduction in relapse rate from Tysabri monotherapy did to EDSS? Also, in the presentation hospitilizations for the Tysabri group were reduced some 50+% relative to the placebo group (this from the slides).

Do you believe Sandrock? Up to you, but hard to believe he would be BSing in a public forum. But how this relates to the FDA-approved label is confusing with regard to the MRIs:

The exact relationship between MRI findings and the clinical status of patients is unknown. Changes in lesion area often do not correlate with changes in disability progression. The prognostic significance of the MRI findings in these studies has not been evaluated.

Confusing to me. Sandrock says MRI and EDSS correlate somewhat in RRMS, yet the Tysabri label does not say this. Big question, unless Sandrock is quoting this with the knowledge that 80% of the AFFIRM EDSS data are in and he knows the results (80% came from the Q&A listening to the link). This is ONLY MY SPECULATION.

Another good piece of news is that Biogen Idec confirmed that the AFFIRM (Tysabri monotherapy) EDSS data WILL be presented at the AAN meeting in early April, 2005.

Sandrock sure uses the words "I think" a lot when he is trying to answer these difficult questions. At this point in time, I really believe that they don't know about the correlation between MRIs, relapses and disease progression measured by EDSS. Not until outsiders view all the data when it's available are we going to get more definitive answers.

Objective: To determine the percentage of patients with residual deficits following multiple sclerosis (MS) exacerbations and the magnitude of those deficits using a database of pooled placebo patients from clinical trials.

Methods: A database of patients assigned to the placebo group in several randomized clinical trials was queried to determine those patients with Expanded Disability Status Scale (EDSS) and Scripps Neurologic Rating Scale assessments prior to, at the time of, and after an acute exacerbation of MS. The extent of deficit present at these time points was compared to determine the acute effect of exacerbations and the degree of persistent disability.

Results: Forty-two percent of patients had residual deficit of at least 0.5 and 28% had residual of 1.0 EDSS units, at an average of 64 days after an exacerbation. The results were reproduced across subsequent exacerbations and were sustained over time. The subgroup of patients with measurable change in EDSS during the exacerbation had more extensive residual impairment on the follow-up visits. Similar results were seen when the Scripps score was examined.

If this is correct, then there is a correlation between relapses and EDSS scores, and the 66% relapse rate reduction of Tysabri could be signficiant in delaying progression. I agree with Harryz, however, need to see the numbers from the trials for confirmation.

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